Mouse Models for Validating Preclinical Candidates for Huntington's Disease

Abstract

Ever since its original description by George Huntington in 1872, Huntington’s disease (HD) has been known as one of the most devastating inherited neurodegenerative disorders afflicting the human brain. Currently in the United States, there are about 30,000 patients with HD and another 150,000 people who are at a genetic risk of developing the disease. HD is characterized by the clinical triad of late-onset motor disturbances (i.e., chorea and dystonia), psychiatric deficits (i.e., depression, irritability, and psychosis), and cognitive decline (Bates et al., 2002). The majority of HD patients experience onset of symptoms around the age of 40 (adult-onset HD), and the disease relentlessly progresses until the patient’s death, which usually occurs within 10–20 years after disease onset. A small subset of HD patients experience the onset of symptoms before age 20 (juvenile HD), and these patients exhibit slightly different clinical features in that they tend to have more dystonia than chorea, as well as a higher incidence of epilepsy. Although the onset of HD is currently defined by the onset of motor deficits, recent studies using more sensitive motor studies, as well as cognitive studies, indicate that clinical manifestations of HD may occur years to decades before the onset of motor symptoms, and such deficits may correspond to the early and progressive cortical and striatal atrophy seen in presymptomatic HD patients (Aylward et al., 2004; Rosas et al., 2005, 2006).